Project 1 In a number animal models of human cognitive impairment there are disturbances in activity-induced remodeling of the dendritic spine actin cytoskeleton and processes of long term potentiation (LTP) that depend upon it. Studies in this program have provided novel evidence that, for several models. Brain-derived neurotrophic factor (BDNF) can rescue both processes. These results suggest that processes on spine actin remodeling represent a final common path impacted in various conditions of cognitive dysfunction and that, through effects on this process BDNF might offset cognitive deficits of different origins. Project 1 will test the hypothesis that increasing brain BDNF levels and signaling will normalize activity-induced spine actin remodeling and LTP in the Fmrl-KO mouse model of Fragile-X Syndrome (FXS) (a mental retardation syndrome with susceptibility for autism spectrum disorder) and in BTBR T* tfl) inbred mice, which exhibit behavioral features of autism. There are 5 specific aims. Aim 1 will test the hypothesis that synaptic BDNF signaling through its TrkB receptor is linked to learning-related activity patterns and enhanced by increased levels of endogenous BDNF. Subaims will test if the frequency sensitivity of TrkB activation depends on mGluRS and NMDA receptors. Aim 2 will identify deficits in TBS-induced signaling contributing to deficiencies in spine F-actin stabilization in Fmrl-KOs and, in particular, if there are impairments in the effects of theta burst afferent stimulation (TBS) on signaling through TrkB, Src and cortactin. Aim 3 will test if BDNF, from exogenous and endogenous sources, restores normal TBS-induced signaling through a proposed spine actin-stabilization pathway (downstream from Cdc42/Rac1) and rescues LTP stabilization in Fmr1-K0 mice. Aim 4 will test if TBS-incduced LTP, and steps in actin signaling that are perturbed in the Fmrl-KO mice, are similarly deranged in BTBR T* tf/J mice and corrected by BDNF. Aim 5 will test if synaptic TrkB receptors are activated (phosphorylated) in hippocampal field CAI in association with unsupervised learning, and if increasing BDNF protein levels leads to greater spine TrkB activation with learning, and reduces behavioral abnormalities, in Fmrl-KO mice. Together these studies will identify mechanisms underlying deficits in LTP stabilization in FXS model mice, determine if the same processes are disturbed in second mouse strain with features of autism, and test if increasing endogenous BDNF is an effective therapeutic strategy for correcting impairments in the cellular mechanisms of learning and memory in these models of cognitive conditions associated with autism. RELEVANCE (See instructions): This project will test if mice with autistic behavioral traits have impairments to the same biological mechanisms underlying learning and memory, as occur in other syndromes of cognitive dysfunction and if well-tolerated drugs causing the brain to increase production of "Brain derived neurotrophic factor" can normalize these biological mechanisms and behavior in these animals. This includes tests to determine if these drugs correct behavioral abnormalities in the mouse model of Fragile X mental retardation syndrome.